Important preparatory steps and clinical considerations for pharmacogenetics adoption into practice

Abstract

Genetic influence on medication response has been well documented; yet, the clinical integration of pharmacogenetics has been slow. Lack of knowledge on the fundamentals of pharmacogenetic testing among clinicians and the complexities surrounding test selection, results interpretation, and clinical utility, among others, contribute to this slow adoption. In this paper, we describe integration of pharmacogenetics in the clinic, selection of target population and testing laboratories, team of expertise needed, available resources, and critical considerations for accurate interpretation of test results. We also discuss phenoconversion and pharmacogenetic utility in special populations including pediatrics, pregnant women and transplant patients. Ultimately, it should be observed that pharmacogenetics is an additional piece in the prescribers’ toolbox to guide prescribing decisions. Other intrinsic and extrinsic factors should be considered for more accurate and personalized prescribing practice. This paper aims to guide clinicians with preparatory steps and “clinical pearls” necessary to successfully integrate pharmacogenetics into routine practice.

Keywords

Pharmacogenomics / pharmacogenetic testing / personalized medicine / precision medicine / phenoconversion / pharmacogenetics in special populations / pharmacogenetics

References

[1] Smith DM,Elsey AR.CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial..Genet Med2019;21:1842-50 PMCID:PMC6650382

[2] Coenen MJ,van Marrewijk CJ.Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease..Gastroenterology2015;149:907-17.e7

[3] Pirmohamed M.Personalized pharmacogenomics: predicting efficacy and adverse drug reactions..Annu Rev Genomics Hum Genet2014;15:349-70

[4] Caudle KE,Hoffman JM.Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process..Curr Drug Metab2014;15:209-17 PMCID:PMC3977533

[5] Hoffman JM,Kevin Hicks J.Developing knowledge resources to support precision medicine: principles from the Clinical Pharmacogenetics Implementation Consortium (CPIC)..J Am Med Inform Assoc2016;23:796-801 PMCID:PMC6080683

[6] Swen JJ,de Boer A.Pharmacogenetics: from bench to byte--an update of guidelines..Clin Pharmacol Ther2011;89:662-73

[7] Manolio TA,Williams MS.Opportunities, resources, and techniques for implementing genomics in clinical care..Lancet2019;394:511-20 PMCID:PMC6699751

[8] Peterson JF,Shi Y.Attitudes of clinicians following large-scale pharmacogenomics implementation..Pharmacogenomics J2016;16:393-8 PMCID:PMC4751074

[9] Frigon MP,Dubois-Bouchard C,Tardif S.Pharmacogenetic testing in primary care practice: opinions of physicians, pharmacists and patients..Pharmacogenomics2019;20:589-98

[10] FDA U. Table of Pharmacogenetic Associations. Available from: https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. [Last accessed on 16 Dec 2020]

[11] Schackman BR,Walensky RP,Freedberg KA.The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV..AIDS2008;22:2025-33 PMCID:PMC2648845

[12] Plumpton CO,Hughes DA.Cost-Effectiveness of Panel Tests for Multiple Pharmacogenes Associated With Adverse Drug Reactions: An Evaluation Framework..Clin Pharmacol Ther2019;105:1429-38

[13] Choi H.Cost-effectiveness of screening for HLA-B*1502 prior to initiation of carbamazepine in epilepsy patients of Asian ancestry in the United States..Epilepsia2019;60:1472-81

[14] Vo TT,Owusu Obeng A,Dunnenberger HM.Pharmacogenomics Implementation: Considerations for Selecting a Reference Laboratory..Pharmacotherapy2017;37:1014-22

[15] Bousman CA,Müller DJ.Navigating the Labyrinth of Pharmacogenetic Testing: A Guide to Test Selection..Clin Pharmacol Ther2019;106:309-12

[16] Pratt VM,Hachad H.Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology..J Mol Diagn2018;20:269-76

[17] Pratt VM,Del Tredici AL.Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists..J Mol Diagn2019;21:746-55 PMCID:PMC7057225

[18] Rescission of Guidances and Other Informal Issuances Concerning Premarket Review of Laboratory Developed Tests. Available from: https://www.hhs.gov/coronavirus/testing/recission-guidances-informal-issuances-premarket-review-lab-tests/index.html. [Last accessed on 16 Dec 2020]

[19] de Leon J.Have we successfully implemented CYP2D6 genotyping in psychiatry?.Expert Opin Drug Metab Toxicol2017;13:1201-3

[20] Bousman C,Müller DJ.Towards the integration of pharmacogenetics in psychiatry: a minimum, evidence-based genetic testing panel..Curr Opin Psychiatry2019;32:7-15

[21] Arwood MJ,Cavallari LH,Duarte JD.Implementing Pharmacogenomics at Your Institution: Establishment and Overcoming Implementation Challenges..Clin Transl Sci2016;9:233-45 PMCID:PMC5121089

[22] Warning Letter Inova Genomics Laboratory. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/inova-genomics-laboratory-577422-04042019. [Last accessed on 16 Dec 2020]

[23] FDA Stepping Up Actions Against PGx Testing, Forcing Some Labs to Stop Reporting Drug Information. Available from: https://www.360dx.com/regulatory-news-fda-approvals/fda-stepping-actions-against-pgx-testing-forcing-some-labs-stop#.X7Kz8ZNKjRY. [Last accessed on 16 Dec 2020]

[24] Roden DM,Mosley JD.Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome..Clin Pharmacol Ther2018;103:787-94 PMCID:PMC6134843

[25] El Rouby N,Langaee T.Clinical Utility of Pharmacogene Panel-Based Testing in Patients Undergoing Percutaneous Coronary Intervention..Clin Transl Sci2020;13:473-81 PMCID:PMC7214641

[26] Dunnenberger HM,Hoffman JM.Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers..Annu Rev Pharmacol Toxicol2015;55:89-106 PMCID:PMC4607278

[27] Manolio TA,Ozenberger B.Implementing genomic medicine in the clinic: the future is here..Genet Med2013;15:258-67 PMCID:PMC3835144

[28] Cicali EJ,Elsey AR.Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene-drug pairs across ambulatory care settings..Genet Med2019;21:2264-74 PMCID:PMC6768772

[29] Cavallari LH,Elsey AR.Institutional profile: University of Florida Health Personalized Medicine Program..Pharmacogenomics2017;18:421-6 PMCID:PMC5558508

[30] Hoffman JM,Wilkinson MR.PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics..Am J Med Genet C Semin Med Genet2014;166C:45-55 PMCID:PMC4056586

[31] Bielinski SJ,Pathak J.Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol..Mayo Clin Proc2014;89:25-33 PMCID:PMC3932754

[32] Van Driest SL,Bowton EA.Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing..Clin Pharmacol Ther2014;95:423-31 PMCID:PMC3961508

[33] Bielinski SJ,Olson JE.Cohort Profile: The Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment Protocol (RIGHT Protocol)..Int J Epidemiol2020;49:23-24k PMCID:PMC7124480

[34] Rosenman MB,Levy KD,Pratt VM.Lessons Learned When Introducing Pharmacogenomic Panel Testing into Clinical Practice..Value Health2017;20:54-9 PMCID:PMC7543044

[35] Chanfreau-Coffinier C,Lynch JA.Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users..JAMA Netw Open2019;2:e195345 PMCID:PMC6563578

[36] Cecchin E,Guchelaar HJ.Ubiquitous Pharmacogenomics (U-PGx): The Time for Implementation is Now. An Horizon2020 Program to Drive Pharmacogenomics into Clinical Practice..Curr Pharm Biotechnol2017;18:204-9

[37] L Rogers S,Giri J.PARC report: a health-systems focus on reimbursement and patient access to pharmacogenomics testing..Pharmacogenomics2020;21:785-96

[38] Ji Y,Blommel JH.Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade..J Mol Diagn2016;18:438-45 PMCID:PMC4851731

[39] Mostafa S,Byron K.An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes..J Neural Transm (Vienna)2019;126:5-18

[40] Cavallari LH.A case for genotype-guided pain management..Pharmacogenomics2019;20:705-8

[41] Cicali EJ,Gong Y.Novel Implementation of Genotype-Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial..Clin Transl Sci2019;12:172-9 PMCID:PMC6440564

[42] Volpi S,Chisholm RL.Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects..Clin Pharmacol Ther2018;103:778-86 PMCID:PMC5902434

[43] Owusu-Obeng A,Hatton RC.Emerging roles for pharmacists in clinical implementation of pharmacogenomics..Pharmacotherapy2014;34:1102-12 PMCID:PMC4188772

[44] Johnson JA.Pharmacists should jump onto the clinical pharmacogenetics train..Am J Health Syst Pharm2016;73:2013-6 PMCID:PMC5359626

[45] Weitzel KW,Langaee TY.Clinical pharmacogenetics implementation: approaches, successes, and challenges..Am J Med Genet C Semin Med Genet2014;166C:56-67 PMCID:PMC4076109

[46] Rafi I,Dawes M,Pirmohamed M.The implementation of pharmacogenomics into UK general practice: a qualitative study exploring barriers, challenges and opportunities..J Community Genet2020;11:269-77 PMCID:PMC7295877

[47] Caudle KE,Whirl-Carrillo M,Relling MV.Evidence and resources to implement pharmacogenetic knowledge for precision medicine..Am J Health Syst Pharm2016;73:1977-85 PMCID:PMC5117674

[48] Bank PCD,Swen JJ.Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group..Clin Pharmacol Ther2018;103:599-618 PMCID:PMC5723247

[49] Caudle KE,Freimuth RR.Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)..Genet Med2017;19:215-23 PMCID:PMC5253119

[50] Caudle KE,Whirl-Carrillo M.Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group..Clin Transl Sci2020;13:116-24 PMCID:PMC6951851

[51] Ross CJ,Sistonen J.The Canadian Pharmacogenomics Network for Drug Safety: a model for safety pharmacology..Thyroid2010;20:681-7

[52] Gaedigk A,Jeong H,Leeder JS.Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics..J Pers Med2018;8:15 PMCID:PMC6023391

[53] Angiolillo DJ,Storey RF.International Expert Consensus on Switching Platelet P2Y₁₂ Receptor-Inhibiting Therapies..Circulation2017;136:1955-75

[54] Shah RR.Addressing phenoconversion: the Achilles’ heel of personalized medicine..Br J Clin Pharmacol2015;79:222-40 PMCID:PMC4309629

[55] Bahar MA,Hak E.Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6..Pharmacogenomics2017;18:701-39

[56] Storelli F,Lenglet S,Desmeules J.Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions..Clin Pharmacol Ther2018;104:148-57

[57] Hicks JK,Sangkuhl K.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors..Clin Pharmacol Ther2015;98:127-34 PMCID:PMC4512908

[58] Lam YW,Ereshefsky L,Simpson J.CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6..Pharmacotherapy2002;22:1001-6

[59] Gaedigk A,Pearce RE,Kennedy MJ.The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype..Clin Pharmacol Ther2008;83:234-42

[60] Crews KR,Dunnenberger HM.Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update..Clin Pharmacol Ther2014;95:376-82 PMCID:PMC3975212

[61] Borges S,Jin Y.Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients..J Clin Pharmacol2010;50:450-8 PMCID:PMC3816977

[62] Hines RN.The ontogeny of drug metabolism enzymes and implications for adverse drug events..Pharmacol Ther2008;118:250-67

[63] Furuta T,Umemura K.Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes..Br J Clin Pharmacol2010;70:383-92 PMCID:PMC2949911

[64] Fernando H,Habersberger J.Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel..J Thromb Haemost2011;9:1582-9

[65] Gage BF,Johnson JA.Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin..Clin Pharmacol Ther2008;84:326-31 PMCID:PMC2683977

[66] Klein TE,Eriksson N.Estimation of the warfarin dose with clinical and pharmacogenetic data..N Engl J Med2009;360:753-64 PMCID:PMC2722908

[67] Gardin A,Legangneux E.Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects..Clin Pharmacokinet2019;58:349-61 PMCID:PMC6373376

[68] Jin Y,Gardin A,Huth F.In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics..Eur J Clin Pharmacol2018;74:455-64 PMCID:PMC5849655

[69] Relling MV,Whirl-Carrillo M.Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update..Clin Pharmacol Ther2019;105:1095-105 PMCID:PMC6576267

[70] Yang JJ,Huang J.The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer..Clin Pharmacol Ther2013;94:252-9 PMCID:PMC3883563

[71] Cheung ST.Mistaken identity: misclassification of TPMT phenotype following blood transfusion..Eur J Gastroenterol Hepatol2003;15:1245-7

[72] Kroon LA.Drug interactions with smoking..Am J Health Syst Pharm2007;64:1917-21

[73] Kato H,Muraki Y.Intravenous Administration of Tacrolimus Stabilizes Control of Blood Concentration Regardless of CYP3A5 Polymorphism in Living Donor Liver Transplantation: Comparison of Intravenous Infusion and Oral Administration in Early Postoperative Period..Transplant Proc2018;50:2684-9

[74] Fleming JN,Taber DJ.Dosing Requirements of Extended-Release Tacrolimus (Astagraf XL) in African American Kidney Transplant Recipients Converted from Immediate-Release Tacrolimus (AAAKTRS)..Ther Drug Monit2020;42:415-20

[75] Hines RN.Ontogeny of human hepatic cytochromes P450..J Biochem Mol Toxicol2007;21:169-75

[76] Helldén A.Pregnancy and pharmacogenomics in the context of drug metabolism and response..Pharmacogenomics2013;14:1779-91

[77] Betcher HK.Pharmacogenomics in pregnancy..Semin Perinatol2020;44:151222 PMCID:PMC7214196

[78] Koren G.Clinical implications of selective serotonin reuptake inhibitors-selective serotonin norepinephrine reuptake inhibitors pharmacogenetics during pregnancy and lactation..Pharmacogenomics2018;19:1139-45

[79] Bell GC,Whirl-Carrillo M.Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron..Clin Pharmacol Ther2017;102:213-8 PMCID:PMC5479760

[80] Tracy TS,Glover DD.Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy..Am J Obstet Gynecol2005;192:633-9